It has been proved that estrogen is biosynthesized from androgen by aromatase enzyme. Accordingly, it is considered that, if aromatase enzyme is effectively inhibited, it must be useful for treatment or prevention of estrogen dependent diseases in mammals such as breast cancer [see Cancer Research, 42, 3261 S (1982)].
In addition to breast cancer, estrogen dependent diseases which can be treated or prevented by an aromatase inhibitor include, for example, endometriosis, cancer of body of uterus, ovary cancer, polycystic ovary syndrome, prostatomegaly and the like. Further, it is considered that an aromatase inhibitor is useful for control of conception. Particularly, in the case of breast cancer, it is said that an aromatase inhibitor can be used instead of a conventional treatment such as ovariectomy, adrenalectomy and the like.
As investigational drugs which are subjected to clinical tests as aromatase inhibitors for the purpose of treatment of breast cancer and the like, there are non-steroidal drugs such as aminoglutethimide, steroidal drugs such as 4-hydroxyandrostenedione, testolactone and the like. However, aminoglutethimide has such a problem that it inhibits various enzymes which pertain to biosynthesis of steroid hormones. And, in the case of steroidal drugs, it is presumed that pharmacological activities characteristic of steroids must be accompanied by side effects.
The present inventors have extensively investigated microbial metabolites to find out a non-steroidal aromatase inhibitor which is different from the above drugs. As the result, the present inventors have succeeded in isolation of a compound having aromatase inhibiting activity, TAN-931 produced by a certain mold and have found that the compound can lower blood estrogen level in mammals. Further, the present inventors have studied the structure of the compound TAN-931 and found that the compound is a novel non-steroidal compound. Furthermore, the present inventors have synthesized its derivatives and have found that they have aromatase inhibiting activity.